Gingivitis, mucosal lesions, and periodontal disease are common and of unknown etiology. It is generally believed that the primary cause of these disorders is a viral infection or immune response, which leads to bacterial infections or anaerobic bacteria, particularly gram-negative anaerobic bacteria, in the mouth. Periodontal disease is a major cause of tooth loss in adults. Periodontal disease affects the periodontum, which is the investing and supporting tissue surrounding a tooth (i.e., the periodontal ligament, the gingiva, and the alveolar bone). Gingivitis and periodontitis are inflammatory disorders of the gingiva and the deeper periodontal tissues, respectively. Gingivitis results from the buildup of dental plaque, and periodontitis is caused by the infection spreading to the periodontal pocket or space between the gingiva and the tooth root. Microorganisms contribute to both the initiation and progression of gingivitis, plaque, and periodontal disease. Thus, in order to prevent or treat these conditions, these microorganisms must be suppressed by some means other than simple mechanical scrubbing.
Other disorders of the mouth, especially the mucosal surfaces, include herpes labialis (cold sores or fever blisters), herpes genitalis, herpes zoster (shingles), varicella zoster (chickenpox); inflammatory diseases and/or diseases demonstrating compromise and/or reaction of the immune system. These include aphthous stomatitis (canker sores), oral mucositis (stomatitis) secondary to chemotherapy, allergic conjunctivitis, giant papillary conjunctivitis; and lesions of injury to the skin including photodermatitis (sunburn, specifically second degree sunburn), thermal burns and pressure sores (decubitus ulcers).
There are a number of over-the-counter medications for cold sores (fever blisters), canker sores, and oral ulcerations and the like, including BLISTEX®, ZILACTIN®, and CAMPHO-PHENIQUE®. However, for many persons suffering from cold sores, fever blisters, etc., these medications are not very effective. A prescription medication also is available, under the trademark ZOVIRAX®. ZOVIRAX® can be effective when taken orally by interfering with the replication of the herpes virus at the genetic level.
Conventional oral hygiene formulations, such as toothpastes (including gels and gels for subgingival application), mouth rinses, mouth sprays, chewing gums, and lozenges (including breath mints) in general, are not very effective in treating oral lesions due to their short contact time with the lesion surface as well as the environment surrounding the lesion in the oral cavity.
The choice of a carrier to be used is determined by the formulation. U.S. Pat. No. 3,988,433 to Benedict describes carriers suitable for toothpastes. U.S. Pat. No. 4,083,955 to Grabenstetter et al. describes carriers suitable for mouth sprays, lozenges, and chewing gums. The main limitation of these formulations is their short contact time, which is typically only a few seconds. Such short contact times are insufficient for treating lesions associated with the disorders described above.
European Patent No. 0 839 524 to Ronchi describes lozenges composed of common antimicrobial agents such as iodine, benzalkonium chloride, and cetylpyridinium chloride. About 99.5% by weight of the lozenge is highly water soluble sugars like glucose and saccharose in combination with less than 0.5% of a bioadhesive polymer. These lozenges do not stock to mucosal tissue as the amount of adhesive polymer is neglible. The lozenges are candies that have some antibacterial agent which is released as the candies dissolve in the mouth.
U.S. Pat. No. 5,456,745 to Rorger describes certain films that swell in aqueous media. The films are prepared by casting an aqueous solution of water soluble anionic polymers, cationic polymers, and a moisturizer into sheets. The films can be prepared by mixing cationic and anionic polymers without precipitation using co-solvents, volatile additives, heat, etc. The films are suggested for use as dressings for damaged skin, such as ulcers of the leg.
U.S. Pat. No. 5,942,244 to Friedman describes non-adhesive tablets that release herbal extracts. Ethyl cellulose is the main polymer component. Ethyl cellulose is a highly hydrophobic polymer that does not interact with hydrophilic surfaces such as mucosa.
U.S. Pat. No. 5,939,050 to Iyer describes various compositions that contain herbal agents. The compositions are not in tablet form and are not bioadhesive.
U.S. Pat. No. 6,207,137 to Shuch et al. describes an orally absorbable dental formulation. The dental formulation includes a base containing Vitamin C at between about 10% and 25% by weight of the composition, and Co-enzyme Q-10 (or ubiquinone), at between 10 and 25% by weight of the composition.
Bioadhesive films prepared by solvent casting from water soluble components are described in U.S. Pat. No. 4,915,948 to Gallopo et al. The water-soluble bioadhesive material used in this device is a xanthan gum or a pectin combined with a polyol.
U.S. Pat. No. 6,159,498 to Topolsky describes a water-soluble pharmaceutical carrier device composed of a layered flexible film having a first water-soluble adhesive layer to be placed in contact with the mucosal surface, a second, water-soluble non-adhesive backing layer, and a pharmaceutical or combination of pharmaceuticals incorporated in the first or second layer. The first water-soluble adhesive layer is hydroxyethyl cellulose, polyacrylic acid, and sodium carboxymethyl cellulose; and the second water-soluble non-adhesive backing layer is hydroxyethyl cellulose.
Solid medications for placement in the oral cavity described in the prior art have been prepared mainly by solvent casting of solutions containing the actives and the polymers to form films, using heat to evaporate the solvent, that are then cut into devices for placement in the oral cavity. This method of preparation is not suitable for herbal extracts and oils that contain volatile active agents which may evaporate during the manufacturing process. Furthermore, exposure of herbal actives to heat during solvent evaporation may degrade the active agents. In addition, this method is very costly and requires a special production line dedicated for film formation. Further, the use of organic solvents such as ethanol and acetone or chlorinated hydrocarbons to dissolve the polymers is expensive and requires collection of the solvent for disposal in order to protect the environment and may require the use of a fire-proof manufacturing site. Solvent residuals in the films may affect the properties of the films and present a risk of contamination to users. Besides the manufacturing problems and high cost, there is also the problem of film scraps left over from the film cutting process. Finally, mucoadhesive polymer films, prepared by film casting, exhibit poor adhesion to mucosal tissue, related to the manufacturing process.
Systemic delivery of drugs and peptides using the buccal route of administration has also been investigated clinically for the delivery of a substantial number of drugs. Buccal administration is the traditional route of administration for nitroglycerin and is also used for buprenorphine and nifedipine. The buccal mucosa is less permeable than the sublingual mucosa. The rapid absorption and high bioavailabilities seen with sublingual administration of drugs is not observed in the buccal mucosa. The permeability of the oral mucosa is probably related to the physical characteristics of the tissues. The sublingual mucosa is thinner than the buccal mucosa; thus permeability is greater for the sublingual tissue. The palatal mucosa is intermediate in thickness, but is keratinized and thus less permeable, whereas the sublingual and buccal tissues are not keratinized. The use of buccal delivery systems for systemic delivery of drugs has been reviewed by Shojaei, J. Pharm. Pharmaceut Sci. 1 (1), 15-30 (1998). A non-degradable device for the delivery of buprenorphine has been described by Guo, Drug Deliv. Ind. Pharmacy, 20, 2809-2821 (1994). The buccal delivery of lidocaine and prostaglandins has been reported by Nagai, J. Controll. Rel. 6, 353-360 (1987).
While buccal delivery systems have been suggested in the prior art, they have been used primarily for the systemic delivery of drugs by taking advantage of the permeability of the mucosal tissue in the mouth to introduce large doses of drugs, mostly peptides and proteins, into the blood system by a non-invasive method. Buccal delivery allows the drug to bypass the gastrointestinal tract, which can degrade drugs which are acid labile and is much less permeable to this class of drugs. Due to the safety risk of systemic uptake of drugs delivered by buccal delivery, the use of natural and safe herbal medications provide an attractive alternative for treating oral ulcers with high patient compliance.
There exists a need for an effective and convenient remedy for the symptoms of viral diseases such as herpes labialis (cold sores or fever blisters), herpes genitalis, herpes zoster (shingles), varicella zoster (chickenpox); inflammatory diseases or diseases comprising the immune system such as aphthous stomatitis (canker sores), oral mucositis (stomatitis) secondary to chemotherapy, allergic conjunctivitis, giant papillary conjunctivitis; and lesions of injury, thermal burns and pressure sores.
It is therefore an object of the invention to provide an improved convenient non-irritating and safe medication and treatment for viral diseases and disorders.